Publications by authors named "Sanjay Thamake"

14 Publications

  • Page 1 of 1

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

N Engl J Med 2021 11;385(22):2036-2046

From the University of Texas M.D. Anderson Cancer Center, Houston (E.J.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (O.I.); Vanderbilt University Medical Center, Nashville (W.K.R.); University of Pennsylvania, Philadelphia (V.K.N.); the University of Utah, Salt Lake City (B.L.M.); Hôpital Européen Georges-Pompidou, University of Paris, Paris (S.O.); the University of Michigan, Ann Arbor (T.E.); the University of Pittsburgh, Pittsburgh (J.K.M.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (S.J.W.); Merck, Kenilworth, NJ (S.T., E.K.P., R.F.P.); and the Center for Cancer Research, National Cancer Institute, Bethesda, MD (W.M.L., R.S.).

Background: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).

Methods: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.

Results: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).

Conclusions: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
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http://dx.doi.org/10.1056/NEJMoa2103425DOI Listing
November 2021

Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.

Nat Med 2021 05 22;27(5):802-805. Epub 2021 Apr 22.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.
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http://dx.doi.org/10.1038/s41591-021-01324-7DOI Listing
May 2021

Rationalizing the use of functionalized poly-lactic-co-glycolic acid nanoparticles for dendritic cell-based targeted anticancer therapy.

Nanomedicine (Lond) 2016 19;11(5):479-94. Epub 2016 Feb 19.

Department of Molecular & Medical Genetics, University of North Texas Health Science Center (UNTHSC), 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.

Background: Delivery of PLGA (poly [D, L-lactide-co-glycolide])-based biodegradable nanoparticles (NPs) to antigen presenting cells, particularly dendritic cells, has potential for cancer immunotherapy.

Materials & Methods: Using a PLGA NP vaccine construct CpG-NP-Tag (CpG-ODN-coated tumor antigen [Tag] encapsulating NP) prepared using solvent evaporation technique we tested the efficacy of ex vivo and in vivo use of this construct as a feasible platform for immune-based therapy.

Results: CpG-NP-Tag NPs were avidly endocytosed and localized in the endosomal compartment of bone marrow-derived dendritic cells. Bone marrow-derived dendritic cells exposed to CpG-NP-Tag NPs exhibited an increased maturation (higher CD80/86 expression) and activation status (enhanced IL-12 secretion levels). In vivo results demonstrated attenuation of tumor growth and angiogenesis as well as induction of potent cytotoxic T-lymphocyte responses.

Conclusion: Collectively, results validate dendritic cells stimulatory response to CpG-NP-Tag NPs (ex vivo) and CpG-NP-Tag NPs' tumor inhibitory potential (in vivo) for therapeutic applications, respectively.
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http://dx.doi.org/10.2217/nnm.15.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563943PMC
December 2016

Radiosynthesis of clinical doses of ⁶⁸Ga-DOTATATE (GalioMedix™) and validation of organic-matrix-based ⁶⁸Ge/⁶⁸Ga generators.

Nucl Med Biol 2016 Jan 1;43(1):19-26. Epub 2015 Sep 1.

ITM Isotopen Technologien München AG, Garching, Germany.

Introduction: 68Ga-DOTATATE is a radiolabeled peptide-based agonist that targets somatostatin receptors overexpressed in neuroendocrine tumors. Here, we present our results on validation of organic matrix 68Ge/68Ga generators (ITG GmbH) applied for radiosynthesis of the clinical doses of 68Ga-DOTATATE (GalioMedixTM).

Methods: The clinical grade of DOTATATE (25 μg±5 μg) compounded in 1 M NaOAc at pH=5.5 was labeled manually with 514±218 MBq (13.89±5.9 mCi) of 68Ga eluate in 0.05 N HCl at 95°C for 10 min. The radiochemical purity of the final dose was validated using radio-TLC. The quality control of clinical doses included tests of their osmolarity, endotoxin level, radionuclide identity, filter integrity, pH, sterility and 68Ge breakthrough.

Results: The final dose of 272±126 MBq (7.35±3.4 mCi) of 68Ga-DOTATATE was produced with a radiochemical yield (RCY) of 99%±1%. The total time required for completion of radiolabeling and quality control averaged approximately 35 min. This resulted in delivery of 50%±7% of 68Ga-DOTATATE at the time of calibration (not decay corrected).

Conclusions: 68Ga eluted from the generator was directly applied for labeling of DOTA-peptide with no additional pre-concentration or pre-purification of isotope. The low acidity of 68Ga eluate allows for facile synthesis of clinical doses with radiochemical and radionuclide purity higher than 98% and average activity of 272±126 MBq (7.3±3 mCi). There is no need for post-labeling C18 Sep-Pak purification of final doses of radiotracer. Advances in knowledge and implications for patient care. The clinical interest in validation of 68Galabeled agents has increased in the past years due to availability of generators from different vendors (Eckert-Ziegler, ITG, iThemba), favorable approach of U.S. FDA agency to initiate clinical trials, and collaboration of U.S. centers with leading EU clinical sites. The list of 68Ga-labeled tracers evaluated in clinical studies should growth because of the sensitivity of PET technique, the simplicity of the shakebake approach for the dose preparation and reliability of 68Ge/68Ga generators. Our studies have confirmed the reproducible elution profile, and high reliability of ITG GmbH generators required for routine doses preparation according to FDA recommendations.
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http://dx.doi.org/10.1016/j.nucmedbio.2015.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538886PMC
January 2016

Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

Nanomedicine (Lond) 2015 ;10(6):915-29

Department of Molecular & Medical Genetics, University of North Texas Health Science Center (UNTHSC), Fort Worth, TX 76107, USA.

Aim: Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating 'bacteriomimetic' nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity.

Materials & Methods: CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo.

Results: We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4(+) and CD8(+) T cell infiltration as well as higher IFN-γ levels as compared with control groups.

Conclusion: Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system.
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http://dx.doi.org/10.2217/nnm.14.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839968PMC
July 2015

Assessment of vulnerable atherosclerotic and fibrotic plaques in coronary arteries using (68)Ga-DOTATATE PET/CT.

Am J Nucl Med Mol Imaging 2015 15;5(1):65-71. Epub 2014 Dec 15.

Excel Diagnostics and Nuclear Oncology Center 9701 Richmond Ave #122, Houston, TX 77042 USA ; RadioMedix, Inc. 9701 Richmond Ave #222, Houston, TX 77042 USA.

Activated macrophages which express somatostatin receptor-2 (SSTR-2) play a vital role in rupture of the vulnerable atherosclerotic plaques, which result in death. (68)Ga-DOTATATE binds to somatostatin receptors 2, and therefore, can serve as potential radiotracer to detect atherosclerotic plaques. The purpose of this study was to generate preliminary data with this agent in vulnerable or fibrotic atherosclerotic plaques in the coronary arteries. We evaluated a total of 44 patients with neuroendocrine tumors (NET) who underwent (68)Ga-DOTATATE PET/CT. In each subject, 7 segments in the coronary arteries were assessed, maximum SUV values and target-to-background ratios (TBRs) were calculated. The lesions detected by CT (a total of 308) were divided into 3 groups based on the Hounsfield unites (HU), and of which, 131 with HU less than 70 were classified as being normal (Control Group), 129 with HU 71-188 as fibrotic plaques (Group 2), and. 48 lesions with HU more than 188 as atherosclerotic plaques (Group 3). The mean TBR value in the normal group was 1.345 ± 0.58 while the mean TBR value in the fibrotic plaque group was 1.752 ± 1.50 (p 0.0043) and in atherosclerotic plaques group was (2.043 ± 1.76, p<0.0001). There was a significant correlation (p=0.0026) between (68)Ga-DOTATATE uptake and the progression to formation of atherosclerotic plaques, based on HU. In patients with neuroendocrine tumors, (68)Ga-DOTATATE PET/CT showed significantly increased uptake in the fibrotic and vulnerable atherosclerotic plaques compared to normal coronary arteries suggesting a potential role of this tracer for molecular assessment of coronary artery disease in this population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299775PMC
January 2015

The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature.

Am J Nucl Med Mol Imaging 2014 15;4(5):426-34. Epub 2014 Aug 15.

Excel Diagnostics and Nuclear Oncology Center 9701 Richmond Ave #122, Houston, TX 77042, USA ; RadioMedix, Inc. 9701 Richmond Ave #222, Houston, TX 77042, USA.

Neuroendocrine tumors (NETs) are rare group of neoplasms arising from nervous and endocrine systems. Somatostatin analogue imaging is a functional imaging modality of choice for evaluating the NETs. Recent availability of positron emitting radioisotope labeled somatostatin analogues to image neuroendocrine cancers, has raised the interests to use this new imaging modality in management of patients with NETs. (68)Ga-DOTATATE PET/CT has demonstrated superiority in lesion detection compared to Octreoscan, MIBG scintigraphy and MRI. In this article, we reviewed the published studies evaluating the role of (68)Ga-DOTATATE PET in diagnosis and management of patients with neuroendocrine tumors and comparing it to current FDA approved imaging modalities including Octreoscan, MIBG scintigraphy, (18)F FDG PET/CT, CT and MRI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138137PMC
August 2014

Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

PLoS One 2012 5;7(9):e44299. Epub 2012 Sep 5.

Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.

Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK), including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR) and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC) patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2), a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044299PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434131PMC
February 2013

A comparative study of phytoestrogen action in mitigating apoptosis induced by oxidative stress.

In Vivo 2012 Sep-Oct;26(5):765-75

Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

The phytoestrogens kaempferol, genistein and genistin were characterized using in vitro assays utilizing iodoacetic acid (IAA)-induced oxidative stress and mitochondrial dysfunction. RGC-5 cells were treated with different concentrations of IAA, and phytoestrogens were administered along with IAA. IAA is cytotoxic to RGC-5 cells and induces the generation of reactive oxygen species (ROS) in vitro. Genistein rescued RGC-5 cells in the presence of IAA, however, it also increased caspase activation and did not inhibit the generation of ROS. Genistein increased phosphorylation of ribosomal s6 kinase (p90RSK), reduced phosphorylation of the ribosomal S6 protein, and had no effect on phosphorylation of protein kinase B (AKT). Kaempferol and genistin rescued RGC-5 cells from IAA-induced cell death, as well as reduced caspase activation and ROS generation. Kaempferol increased phosphorylation of AKT and MAP kinase (p44/42). Genistin reduced phosphorylation of p42 and p90RSK. Although these phytoestrogens are flavonoids and similar in structure, they exhibit different effects on cell signaling.
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January 2013

Alendronate coated poly-lactic-co-glycolic acid (PLGA) nanoparticles for active targeting of metastatic breast cancer.

Biomaterials 2012 Oct 12;33(29):7164-73. Epub 2012 Jul 12.

Department of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

Delivery of therapeutic agents to bone is crucial in several diseases such as osteoporosis, Paget's disease, myeloproliferative diseases, multiple myeloma as well as skeletal metastasizing cancers. Prevention of cancer growth and lowering the cancer induced bone resorption is important in the treatment of bone metastasizing cancers. Keeping in mind the low diffusivity and availability of cell surface targets on cancer cells, we designed a targeted system to deliver chemotherapeutic agents to the bone microenvironment as an approach to tissue targeting using alendronate (Aln). We co-encapsulated curcumin and bortezomib in the PLGA nanoparticles to further enhance the therapeutic efficiency and overall clinical outcome. These multifunctional nanoparticles were characterized for particle size, morphology and drug encapsulation. The particles were spherical with smooth surface and had particle size of 235 ± 70.30 nm. We validated the bone targeting ability of these nanoparticles in vitro. Curcumin and bortezomib are known to have synergistic effect in inhibition of growth of cancer; however there was no synergism in the anti-osteoclastogenic activity of these agents. Surprisingly, curcumin by itself had significant inhibition of osteclastogenic activity. In vivo non-invasive bioimaging showed higher localization of Aln-coated nanoparticles to the bone compared to control groups, which was further confirmed by histological analysis. Aln-coated nanoparticles protected bone resorption and decreased the rate of tumor growth as compared to control groups in an intraosseous model of bone metastasis. Our data show efficient attachment of Aln on the surface of nanoparticles which could be used as a drug carrier for preferential delivery of multiple therapeutic agents to bone microenvironment.
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http://dx.doi.org/10.1016/j.biomaterials.2012.06.026DOI Listing
October 2012

A sustained release formulation of chitosan modified PLCL:poloxamer blend nanoparticles loaded with optical agent for animal imaging.

Nanotechnology 2011 Jul 21;22(29):295104. Epub 2011 Jun 21.

Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

The objective of this study was to develop optical imaging agent loaded biodegradable nanoparticles with indocynanine green (ICG) using chitosan modified poly(L-lactide-co-epsilon-caprolactone) (PLCL):poloxamer (Pluronic F68) blended polymer. Nanoparticles were formulated with an emulsification solvent diffusion technique using PLCL and poloxamer as blend-polymers. Polyvinyl alcohol (PVA) and chitosan were used as stabilizers. The particle size, shape and zeta potential of the formulated nanoparticles and the release kinetics of ICG from these nanoparticles were determined. Further, biodistribution of these nanoparticles was studied in mice at various time points until 24 h following intravenous administration, using a non-invasive imaging system. The average particle size of the nanoparticles was found to be 146 ± 3.7 to 260 ± 4.5 nm. The zeta potential progressively increased from - 41.6 to + 25.3 mV with increasing amounts of chitosan. Particle size and shape of the nanoparticles were studied using transmission electron microscopy (TEM) which revealed the particles to be smooth and spherical in shape. These nanoparticles were efficiently delivered to the cytoplasm of the cells, as observed in prostate and breast cancer cells using confocal laser scanning microscopy. In vitro release studies indicated sustained release of ICG from the nanoparticles over a period of seven days. Nanoparticle distribution results in mice showing improved uptake and accumulation with chitosan modified nanoparticles in various organs and slower clearance at different time points over a 24 h period as compared to unmodified nanoparticles. The successful formulation of such cationically modified nanoparticles for encapsulating optical agents may lead to a potential deep tissue imaging technique for tumor detection, diagnosis and therapy.
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http://dx.doi.org/10.1088/0957-4484/22/29/295104DOI Listing
July 2011

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events.

J Cell Sci 2011 May 12;124(Pt 9):1453-64. Epub 2011 Apr 12.

Department of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

Extracellular proteolysis is an indispensable requirement for the formation of new blood vessels during neovascularization and is implicated in the generation of several angiogenic regulatory molecules. Anti-proteolytic agents have become attractive therapeutic strategies in diseases associated with excessive neovascularization. Annexin A2 (AnxA2) is an endothelial cell-surface receptor for the generation of active proteolytic factors, such as plasmin. Here, we show that AnxA2 is abundantly expressed in the neovascular tufts in a murine model of neovascularization. Exposure to hypoxic conditions results in elevation of AnxA2 and tissue plasminogen activator (tPA) in human retinal microvascular endothelial cells (RMVECs). We show that the hexapeptide competitive inhibitor LCKLSL, which targets the N-terminal tPA-binding site of AnxA2, binds efficiently to cell-surface AnxA2 compared with binding of the control peptide LGKLSL. Treatment with the competitive peptide inhibits the generation of plasmin and suppresses the VEGF-induced activity of tPA under hypoxic conditions. Application of the competitive peptide in two in vivo models of angiogenesis demonstrated suppression of the angiogenic responses, which was also associated with significant changes in the vascular sprouting. These results suggest that AnxA2-mediated plasmin generation is an important event in angiogenesis and is inhibited by a specific competitive peptide that inhibits the binding of tPA to AnxA2.
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http://dx.doi.org/10.1242/jcs.079236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078813PMC
May 2011

Studies on solvatochromic properties of aminophenylstyryl-quinolinum dye, LDS 798, and its application in studying submicron lipid based structure.

Biophys Chem 2010 Dec 13;153(1):61-9. Epub 2010 Oct 13.

Center for Commercialization of Fluorescence Technologies, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.

The styryl group of dyes has been used in cellular studies for over 20 years because of their solvatochromic and/or electrochromic properties. Here we report characterization of solubility and solvatochromic properties of a near infra-red styryl dye, styryl 11 or LDS 798. We have extended our studies to small unilamellar vesicles and lipid based nanoparticles and found that solvatochromic properties of this dye used in tandem with fluorescence correlation spectroscopy can be used to efficiently determine the diffusion coefficient and hence the size of the submicron lipid based particles. This technique has the potential to provide essential information about liposomal and vesicular structures and their movement in vitro and in situ.
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http://dx.doi.org/10.1016/j.bpc.2010.10.005DOI Listing
December 2010
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